Research On The Function Of β-catenin In The Individual Development At Postnatal Stage

P-catenin is a glycoprotein with dual function, as a component of adherens junctions and also a key factor of canonical Wnt signaling. It plays an important role in oncogenesis, stem cell differenciation, embryonic development and adult homeostasis. Due to the extensive function of the canonical Wnt signaling mediated by β-catenin, the embryonic deletion of β-catenin leads to the prenatal death, which make it impossible to study the fuction of β-catenin in the postnatal stage. By using Cre-LoxP gene recombination strategy, we generated the CamKⅡα-iCre; β-catenin flox/flox conditional knockout (β-catenin CKO) mice in which β-catenin expression is specifically deleted from the forebrain cells during the perinatal period. It turns possible to study the role of β-catenin in the maintain of hippocampal primordium at perinatal stage and the formation of hypothalamus feeding neural circuits at postnatal stage. It includes two parts:(1) In mice, the compact hippocampal primordium is formed during the prenatal stage by early-generated precursor cells and granule neurons that migrate from the lateral ventricle zone. The molecular mechanisms that maintain the morphology of the hippocampal primordium after its formation remain to be characterized. Previous embryonic deletion studies have demonstrated that β-catenin is required for generation of granule cells. But whether β-catenin is involved in the morphological maintenance of the hippocampus as a cell adhesion molecule is still elusive. Herein, our CamKⅡα-iCre; β-cateninflox/flox conditional knockout mice realize perinatal deletion of P-catenin in some radial glial cells of hippocampus. At embryonic day18th (E18), some GFAP-expressing cells inserted the primodium at the boundary of dentate gyrus and CA3domain, followed by the disorganization of radial glial scaffold, appearance of some ectopic cells and consequential severe defects in hippocampal morphology. Interestingly, the expression and distribution of reelin, which guides the cell migration, were normal at E18. We demonstrate that β-catenin is required for maintaining radial glial scaffold possibly via its well-known role in cell adhesion during the perinatal period. These findings give essential advances into the maintaining of hippocampal primordium at perinatal period.(2) Arcuate nucleus of hypothalamus (ARC) is the core component in the regulation circuits of food intake and energy homeostasis. ARH projections to other parts of the hypothalamus and to extrahypothalamic areas are established in the postnatal two weeks, which is a pivotal stage for individual development. Whether β-catenin plays any roles in the development of hypothalamus is not clear. According to our observation, perinatal conditional knockout of β-catenin by CamKIIa-Cre in forebrain reduces body weight gain from P8and dramatically shortens life span. Quantitative PCR and in situ hybridization results showed the expression of NPY mRNA in the ARH of β-catenin CKO mice at P15is obviously increased compared with that of littermate controls, whereas the expression of POMC mRNA is significantly decreased, which suggested the reduction of postnatal body weight gain might be due to the deficiency of food intake. In addition, the immunochemistry staining for NPY and c-Fos induced by leptin suggest the normal projection of ARC neurons to PVH and DMH. Together, P-catenin might play an important role in the regulation of food intake and postnatal body weight gain probably through affecting the development of extrahypothalamic ARH circuits.